The proposal aims at addressing the burden of disease, risk factorsfor and potential to intervene against neonatal and maternalperi-partum sepsis in a developingcountry setting with a high prevalence(29%)of maternal HIV infection. The study site is a secondary-tertiary hospital in Johannesburg, South Africa. The primary aim of this proposal is to complete a currently underwaydouble-blind randomizedplacebo controlled trial studying the efficacy of chlorhexidine (0.5% solution) intavaginal washes during labor in the mother and subsequentcleansing of the newborn with full-body chlorhexidine wipes, to prevent early -onset (within 72 hours of birth) neonatal sepsis and peri-partum (within 14 days of birth) sepsis in the mother. Based on an estimatedincidence rate of 30 cases of sepsis/1000 life births occuring within 72 hours of birth, we proposeto randomise 8 000 women during labor into one of two arms (chlorhexidine vs. autoclaved tap- water inetnmittent vaginal washes) to detect at least a 40% reduction in the incidence of neonatal sepsis, with 80% power and 95% confidence. The study-outcome measureof neonatalsepsiswill include culture confirmed disease and/or a clinical diagnosis of sepsis based on an algorithm that has been agreed upon by experts in the field. We also plan to measure in a subset of mother-infant pairs the prevalence of vaginal colonisation by bacteria in the mother during labor and the impact of the study-intervention on the incidence of colonisation of the newborn with vaginal bacterial flora. The study will evaluate the effect of the intervention on the incidence of the following specificoutcomes: Primary objectives: 1. Early (within 72 hours of birth) microbiologiocally confirmed and/ or clinically diagnosed neonatalsepsis. 2. Decrease in vertical transmission of colonization with Group B Streptococcus from the mother to the newborn. Secondary objectives: 1. Incidence of community-acquired neonatal sepsis/meningitis between72 hours and 28 days of life. 2. Incidence of peripartum culture-confirmedor clinically diagnosed maternal sepsis within 14 days fo birth. 3. Incidence of colonization of the newbornwith Klebsiela pneumoniaeand E . coli. 4. The burden of disease and risk factors for maternal peripartum infection and serious neonatal infections in SouthAfrica with emphasis on the impact of maternalHIV infection on these outcomeswill also be studied. Relevance: The findings from this study may contribute in sari to realising one of the Millenium goals of the United Nations; i.e. to halve childhood mortality by2015. The leading cause of neonatal deaths, which contribute to at least one-third of all infant deaths, in developing countries are sepsis and birth asphyxia. Logistical and resource constraints in developing countries prohibit the implementation of strategies that have been successfully in developed countries to reduce neonatal sepsis, therefore a more practical and affordable solution is required for developing countries. PERFORMANCE S(TE(S) (organization, city, state) University of Witwatersrand/Medical Research Council Respiratory and Meningeal Pathogens ResearchUnit Chris Hani Baragwananth Hospital, Old Potch Road, Soweto, Gauteng, South Africa The study is to be done in Soweto, which is situated in central South Africa in a province called Gauteng. This is an urban African township with an estimated population of 1.2-1.5 million people in an area of 78 square kilometers. Soweto is the largest Arican township in South Africa and has 29 districts with approxiamtely 50-300 000 people residing in each district. Most residents reside in a variety of dwellings ranging from single sex hostels and informal shack settlements (26%) to formal brick housing (58%). Residents in Soweto have access to potable water in their yards (59%), or homes (35%), or community taps (6%). One in 10 adults in Soweto has no formal education and a quarter have a maximum of seven years of education. Nearly 42% of adult Sowetans are unemployed. The community has been highly affected by HIV, with 30% of pregnant women that attend antenatal clinics testing positive for HIV. Annually there are 30000 births in the area, with at least 18 000 of these occuring at the only public hospital in the area, viz. Chri Hani- Baragwanath hsoprtal (CHBH). Over 90% of expectant mothers have at least one antenatal visit prior to delivering, of whom more than 95% consnet to HIVtesting. Health care for expectant mothers and their newboms is free of charge at all government hearth facilities. PHS 398 (Rev. 0004) Page 2 Form Page 2 Principal Investigator/Program Director (Last, First, Middle): Madhi, Shabif Ahmed KEY PERSONNEL See instructions. Usecontinuationpages as neededto provide the required information in the formal shown below. Start with Principal Investigator. List all other keypersonnel in alphabetical order, last name first Name eRA Commons User Name Organization Role on Project Madhi, ShabirAhmed RMPRU Principal Investigator Adrian, PeterVincent RMPRU Laboratory scientist Cutland, Clare Lousie RMPRU Study team-leader Velaphi, Sithembiso Univ of Wrtwatersrand Co-investigator OTHER SIGNIFICANT CONTRIBUTORS Name Buchman, Eckard Hofmeyr, Justice Klugman, Keith P Miotti, Pallo Pattinson, Robert Saloojee, Haroon Temmermann, Marieen Violari, Avye Organization Univ of Wrtwatersrand,Obstetrics Univ of Wrtwatersrand, Effective Care Emory University, School of Public NIH/DAIDS University of Pretoria, Obstetrics Univ of Wrtwatersrand,CommPaeds University Hospital, Ghent Perinatal HIV research unit Wits Role on Project Consultant Advisor (SSC) Advisor (SSC) Advisor (SSC) Advisor (SSC) Advisor (SSC) Advisor (SSC) Consultant Human Embryonic Stem Ceils ^ No D Yes If the proposed project involves human embryonic stem cells, list below the registration number of the specific cell line(s) from thefollowing list: http://Stemcells.nih.gov/registrv/index.asp. Usecontinuationpages as needed. If a specific line cannot be referenced at this time, include a statement that onefromthe Registry will beused. Ceil Line Disclosure Permission Statement Applicable to SBIR/STTR Only. SeeSBIR/STTR instructions. EH Yes No PHS 398 (Rev. 09/04) Page 3 Form Page 2-continued Number the fdloinng pages consecutivelythroughout the application. Do not use suffixes suchas 4a, 4t>. Principal Investigator/Program Director (Last, First, Middle): Madhi, Shabil" Ahmed The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page 1 Description,